Intrastriatal infusion of the potent dopaminergic trophic factor GDNF promotes significant behavioral improvements in animal models of Parkinson's disease. The mechanisms of action are not fully understood, but include the upregulation of nigrostriatal dopaminergic functions, neuroprotection against some neurotoxins, and over a period of weeks to months, structural restoration on the nigrostriatal dopaminergic system. Another possible mechanism, with extraordinary implications if substantiated, is the neurogenesis of nigral dopamine neurons. The studies in Project 3 focuse on answering three major questions. 1) What is the role of neurogenesis and/or gliogenesis in GDNF- induced functional recovery of the nigrostriatal system? Experiments are designed to critically test the hypothesis that neurogenesis is a principal component of functional recovery in the substantia nigra and putamen. 2) To what extent does GDNF therapy restore normal nigrostriatal dopaminergic circuitry? Structural restoration will be correlated with the measures of functional restoration quantified in Projects 1 and 2 to critically test the hypothesis that the extent of motor behavior recovery in parkinsonian rhesus monkeys receiving GDNF therapy is directly correlated to the structural restoration of the nigrostriatal dopaminergic system. 3) To identify and analyze possible neuropatholoqical sequellae arising from intracerebral GDNF treatment. Antibodies to GDNF have been detected in some advanced Parkinson's disease patients receiving intracerebral administration of the trophic factor. The effects of circulating GDNF antibodies on the adult primate nervous system are not known. Thehypothesis being tested in this specific aim is that there is not anautoimmune loss of GDNF-responsive neurons in adult primates with circulating GDNF antibodies. Five populations of GDNF-responsive neurons will be evaluated in rhesus monkeys receiving intracerebral infusions of GDNF or vehicle. Three of the neuronal populations are in the CNS: midbrain dopamine neurons, Purkinje cells in the cerebellum and motor neurons in the cervical spinal cord. The other two neuronal types are in the PNS: dorsal root ganglion neurons and enteric neurons in the gastrointestinal system.